title: Protection of murine neural progenitor cells by the Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin in the low nanomolar concentration range.
abstract: Stem cell-based approaches provide hope as a potential therapy for neurodegenerative diseases and stroke. One of the major scientific hurdles for stem cell therapy is the poor survival rate of the newly formed or transplanted neural stem cells. In this study, we found that low-dose treatment with the Heat shock protein 90 (Hsp90) inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG), a heavily investigated anti-cancer drug, prevented neural progenitor cells from either naturally-occurring or stress-induced apoptosis, although it induced apoptosis at higher doses. This stress adaptation effect mediated by low-dose 17-AAG is accompanied by activation of multiple cell survival pathways, including the stress response pathway (induction of Hsp70), the MAPK pathway, and the PI3K/Akt pathway. When administered in vivo, 17-AAG led to Akt and glycogen synthase kinase 3β phosphorylation, and more 5-bromo-2'-deoxyuridine positive cells in the mouse brain. These findings could have profound implications in stem cell therapy for neurodegenerative diseases and stroke.
authors.affiliation: Institute of Molecular Medicine and Genetics, Medical College of Georgia, Georgia Health Sciences University, Augusta, Georgia 30912, USA. gwang@georgiahealth.edu
authors.forename: Guanghu
authors.initials: G
authors.lastname: Wang
authors.forename: Kannan
authors.initials: K
authors.lastname: Krishnamurthy
authors.forename: Dantera
authors.initials: D
authors.lastname: Tangpisuthipongsa
mesh_terms: D000818:Animals; D000963:Antimetabolites; D016227:Benzoquinones / Q000008:administration & dosage / Q000494:pharmacology*; D015153:Blotting, Western; D001973:Bromodeoxyuridine; D016923:Cell Death / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects; D005455:Fluorescent Antibody Technique; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D047029:Lactams, Macrocyclic / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D058953:Neural Stem Cells / Q000187:drug effects*; D018696:Neuroprotective Agents; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000963:Antimetabolites; D016227:Benzoquinones; D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D018696:Neuroprotective Agents; C112765:tanespimycin; D012313:RNA; D051057:Proto-Oncogene Proteins c-akt; D001973:Bromodeoxyuridine; C001277:geldanamycin